Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease.

In this study we report that the membrane-bound, but not cytosolic insulin degrading enzyme (IDE) protein concentration and IDE activity are significantly decreased in the hippocampal formation of cases affected by mild cognitive impairment (MCI) which are at high risk to develop Alzheimer's disease (AD), relative to normal neurological controls. Membrane-bound IDE protein concentrations and activity in the hippocampal formation continued to decrease during the conversion from MCI to mild-severe AD. This selective decrease in hippocampal membrane-bound, but not cytosolic, IDE concentration and activity was tissue specific since no changes in either membrane-bound or cytosolic IDE were found in the occipital cortex of the same cases examined. Most interestingly, the decreased hippocampal membrane-bound IDE protein activity negatively correlated with brain beta-amyloid (Abeta)X-42 content in MCI and in AD brain. The study tentatively suggests that interventions aimed at promoting membrane-bound IDE activities in the brain of MCI cases may help to prevent the onset and possibly the progression into AD through mechanisms involving the clearance of monomeric Abeta from the brain.

Caloric intake and Alzheimer's disease. Experimental approaches and therapeutic implications.

Alzheimer's disease (AD) is a rapidly growing public health concern with potentially devastating effects. Presently, there are no known cures or effective preventive strategies. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset sporadic AD cases, the most common form of AD. Due to the fact that the disease typically strikes very late in life, delaying symptoms could be as good as a cure for many people. For example, it is now widely accepted that if the onset of the disease could be delayed by even 5 years, the incidence could be cut in half. Both clinical and epidemiological evidence suggests that modification of lifestyle factors such as nutrition may prove crucial to AD management given the mounting experimental evidence suggesting that brain cells are remarkably responsive to "what somebody is doing". Among other nongenetic factors influencing AD, recent studies strongly support the evidence that caloric intake may play a role in the relative risk for AD clinical dementia. Indeed, the effect of diet in AD has been an area of research that has produced promising results, at least experimentally. Most importantly, as mechanistic pathways are defined and their biochemical functions scrutinized, the evidence supporting a direct link between nutrition and AD neuropathology continues to grow. Our work, as well as that of others, has recently resulted in the development of experimental dietary regimens that might promote, attenuate or even reverse features of AD. Most remarkably, while we found that high caloric intake based on saturated fat promotes AD type Beta-amyloidosis, conversely we found that dietary restriction based on reduced carbohydrate intake is able to prevent it. This evidence is very exciting and is, in part, consistent with current epidemiological studies suggesting that obesity and diabetes are associated with a >4-fold increased risk of developing AD. The clarification of the mechanisms through which dietary restriction may beneficially influence AD neuropathology and the eventual discovery of future "mimetics" capable of anti-Beta-amyloidogenic activity will help in the development of "lifestyle therapeutic strategies" in AD and possibly other neurodegenerative disorders.

Is there a future for cyclo-oxygenase inhibitors in Alzheimer's disease?

Several epidemiological studies have indicated that the long-term use of NSAIDs, most of which are cyclo-oxygenase (COX) inhibitors, may reduce the risk of Alzheimer's disease. For this reason, anti-inflammatory COX-inhibiting NSAIDs have received increased attention in experimental and therapeutic trials for Alzheimer's disease. However, several recent efforts attempting to demonstrate a therapeutic effect of NSAIDs in Alzheimer's disease have largely failed. Clinicians and scientists currently believe that this lack of success may be attributable to two key problems: (i) clinical trials of NSAIDs have been conducted in patients with late-stage Alzheimer's disease, wherein advanced neurodegeneration may be refractory to anti-inflammatory drug treatment; and (ii) it is not known which of the large family of NSAIDs (i.e. COX-1, COX-2 or mixed inhibitors) is most efficacious in preventing Alzheimer's disease. The wide list of putative functions for COX in the brain, and the significant functional heterogeneity of NSAIDs, which appear to influence the beta-amyloid (Abeta) neuropathology associated with Alzheimer's disease via both COX-dependent and COX-independent pathways, complicate the interpretation of the mechanisms through which COX-inhibiting NSAIDs may beneficially influence Alzheimer's disease. As discussed in this review, for patients at high risk of developing Alzheimer's disease (e.g. those with mild cognitive impairment), preventative treatment with COX-inhibiting NSAIDs may ultimately represent a viable strategy in the management of clinical Alzheimer's disease. However, the recent evidence showing an increased risk of major cardiovascular events among patients treated with certain COX-1 and COX-2 inhibitors leaves many questions unanswered. We suggest that further investigation into the physiological role(s) of COXs in normal health and in disease conditions, and the identification of safer and better tolerated COX inhibitors, will provide renewed impetus to the application of anti-inflammatory strategies for the prevention and treatment of Alzheimer's disease.